JPS6021983B2 - New pyridazinylhydrazones and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel pyridazinylhydrazones and physiologically acceptable salts thereof.

The invention also relates to processes for making these compounds. Specifically, the present invention relates to novel pyridazinylhydrazones having the following general formula 1 and physiologically acceptable salts thereof.

In the above formula, RI represents hydrogen, chlorine, a morpholine ring or an N-methylpiverazine ring, Q is a bicycloalkylidene having 6 to 1 hard carbon atoms, a cycloalkylidene having 4 to 1 hard carbon atoms, 4 to 1 hard carbon atoms, represents a cycloalkenylidene having 8 carbon atoms or an alkylidene having 1 to 4 carbon atoms substituted by a bicycloalkenyl having 6 to 8 carbon atoms, R2 is hydrogen, 1
alkyl, carboxyl or group having ~4 carbon atoms: -COOR4, where R4 represents alkyl having 1 to 4 carbon atoms, R3 is hydrogen, 1
or 2 alkyl having 1 to 4 carbon atoms or alkenyl having 2 to 6 carbon atoms.

It is well known that norepinephrine is the most important blood pressure regulator in humans and higher animals {S. M. Rapopore, Med. BiMhemi
e, VEB Verlag Volk un
dQs Gajieit, Berlin, 720 (1965)}.

Therefore, pathological hypertension is lowered by inhibition of noradrenaline biosynthesis {0. Schier and ANnerxer, Arzneimitte breast rschung,
13, Birkhauser Verlag, Basel, p. 107 (1969)}. The first step of this biosynthesis consists of the hydroxylation of tyrosine with the enzyme tyrosine hydraxylase acting as a biocatalyst, while the third step is in the presence of the enzyme dopamine-8-hydroxylase as a biocatalyst. Dopamine is 8-hydroxylated. Surprisingly, the novel pyridazinylhydrazone derivatives having the general formula 1 exhibit significant tyrosine hydroxylase and dopamine-8-hydroxylase inhibitory effects, thereby inhibiting the biosynthesis of noradrenaline and causing significant and persistent effects. It was unexpectedly discovered that it exhibits antihypertensive activity.

Compounds having general formula 1 and physiologically acceptable salts thereof are:
According to the present invention, a compound having the following general formula 0: [In the above formula, RI represents the same thing as defined above] is prepared by the following general formula m: [In the above formula, R2 and R3 have the same meaning as defined above] If desired, the resulting acid in which R2 is a carboxyl group in the general formula 1 or its reactive conductor can be reacted with a ketone having the general formula:
40 days (wherein R4 represents the same thing as defined above), in general formula 1, R2 is -COOR4 group (herein R4 represents the same thing defined above). The compound is prepared by preparing the compound and, if desired, converting the obtained compound of general formula 1 into a physiologically acceptable acid addition salt thereof.

According to a preferred embodiment of the invention, the compounds of general formulas 0 and m are prepared by combining the two reactants in water or an organic solvent, preferably an ether such as diethyl ether or tetrahydrofuran, a lower aliphatic The compounds of general formula 1 are modified by reaction in alcohols or aromatic hydrocarbons such as benzene, toluene, or xylene.

In some cases it may be advantageous to add an acid catalyst to the reaction mixture, for example 4-toluenesulfonic acid or hydrochloric acid. Among the starting materials having the general formula 0, the following compounds are described in the literature: 3-chloro-6-pyridazinylhydrazine {Yakugakunesshi, Vol. 75,
778 (1955);C. A, 50 volumes, 497 valence (19
56)}, 3-pyridazinylhydrazine {Bull. s
M. chim. France, 1793 (1959)}
, and ami/substituted pyridazinylhydrazines {e.g.
J. Med. Chem-, 1 nephew, 741 (1975)
}.

From compounds of general formula m, cycloalkanone derivatives substituted with an alkoxycarbonyl group in the 2-position are prepared by reacting the corresponding cycloalkanone with an alkyl oxalate in the presence of sodium alcoholate. {For example, see orgS to th volume 0, 531}
. Compounds in which R2 is hydrogen in the general formula are readily commercially available cyclic ketones such as camphor, carvone, or 2-methylcyclohexanone.

Compounds in which R2 is a carboxyl group in the general formula m are usually prepared by mild alkaline hydrolysis of the corresponding carboxylic acid ester {see, for example, J. Am. Chem
．． S ratio. , vol. 81, 25 moth (1959): Liebi bag A skin. , vol. 699, 33 (1966) and vol. 317, Satoshi (1901): Chem. Be. , 72 lids, 919 (
1939)}.

Compounds in which R2 is a carboxyl group in General Formula 1 are as follows: In General Formula 1, R2 is -CO
Preferably, it is modified into a compound having an OR4 group.

If carboxylic acid esters, ie compounds in which R2 is one C02R4, are to be prepared, in a first step the acid of general formula 1 is converted to its acid chloride with thionyl chloride.

As a solvent, an excess of thionyl chloride can be used and the reaction can be carried out in a chlorinated hydrocarbon such as chloroform or dichloroethane or a hydrocarbon such as benzene. The resulting acid chloride is then treated with an alcohol having the general formula R40 or an alkali metal alcoholate with this alcohol, preferably in an excess amount of the alcohol.
The reaction is carried out at a temperature between 0°C and the boiling point of the alcohol. If methyl or ethyl esters are to be produced, this can also be done by reacting an acid having the general formula 1 with methanol or ethanol containing gaseous hydrochloric acid.

Compounds of general formula 1 can be prepared by dissolving the base of general formula 1 in, for example, ether, methanol, ethanol or isoprobanol, and adding a solution of the corresponding inorganic acid in methanol, ether/ether or methanol to the resulting solution. Preferably, they are converted into their acid addition salts by adding dropwise, with cooling, a solution of the appropriate organic acid in ethanol, isopropanol, ether or acetone.

The precipitate is separated by furnace and recrystallized if necessary. Representative examples of suitable inorganic acids include hydrochloric acid, hydrogen bromide, sulfuric acid,
It is phosphoric acid.

Tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, ethanesulfonic acid and 4-toluenesulfonic acid are advantageously used as organic acids. Tyrosine hydroxylase inhibitory activity (TH inhibitory activity) of the novel compound according to the present invention,
Nagatsu's method for Liu Xian homogeneity in rats {
AMI. Biochem. , Volume 9, 122 (1964)
} was tested in vitro.

Radioactive tyrosine was produced by a method developed by Robert J.
Biol. Chem. , vol. 241, 4452 (1966
)} was purified. Rat wealth. Wise homogeneous TH
Activity is 0.64 soil 8 nmoles / soil protein / 6 molecules
The amount was n. Dopamine-B- of the compound according to the present invention
Hydroxylase inhibitory activity (DBH inhibitory activity) was determined using the modified Nagatsu method {B. B. A
cta, 139, 319 (1967)}.

The specific activity of bovine adrenal preparation is 780±50 mmoles/
It was recognized that it was a ground protein/6-hin. The inhibitory effects of some compounds encompassed by general formula 1 are listed in Table 1 below in comparison with some compounds.

Table I The antihypertensive activity of the novel compounds of the present invention was evaluated in spontaneously hypertensive rats (Wistar 10kamoto rats).
On the other hand, Arzn. To Fo Daich, Volume 6, Volume 2, Shigeru (1956)
) Tested according to the method described in .

The systolic blood pressure of conscious animals was measured at
Measurements were taken in the caudal artery after 2448 and 7 hours. The results obtained are shown in Table 0' below. Among the test compounds, the compounds of Examples 10 and 15 showed significant hypotensive activity (15% or more).

The oral acute toxicity and therefore therapeutic index of these compounds to rats are also favorable. Biochemical and pharmacological experiments show that it exhibits a long-lasting and potent hypotensive effect along with a strong enzyme inhibitory activity.

Compounds of general formula 1 can be used therapeutically in doses of 50 to 300 mo per day. The invention is explained in more detail in the following examples.

Note that these examples are not intended to limit the present invention. Example 1 1,7,7-trimethyl-2-picyclo[2,2,1]
Heptylidene-(3-chloro-6-pyridazinyl)hydrazone method [a} 30.4 mol (0.2 mol) of camphor, 29 mol (0.2 mol) of 3-chloro-6-pyridazinylhydrazine, 500 mol of A mixture of ethanol and 50' triK acetic acid was held at boiling temperature for 3 hours.

The solvent was then distilled off in vacuo and the evaporation residue was mixed with 200 g of water and neutralized with 10% sodium carbonate solution under cooling. The obtained precipitate was separated by furnace, washed with water until it became neutral, and dried. Recrystallized from ethanol to give 103~
The compound in question has a melting point of 105°C.
．． 5%). The hydrochloride salt of the resulting product was prepared by suspending the base in ether and saturating the suspension with gaseous dry hydrochloric acid.

The precipitate formed was filtered out, washed with ether, and dried.
The melting point of the acid addition salt obtained was 178°C (decomposed).
Method 'b' 3.04 mol (20 mmol) of camphor, 2.9 mol (20 mmol) of 3-chloro6-pyridazinylhydrazine,
A mixture of 50 volumes of ethanol and 2 drops of concentrated hydrochloric acid solution is added to 1
Boil for half an hour.

102-105 according to the operations described in the method.
3.2 volumes (57%) of the title compound with a melting point of q0 were obtained. Method [c-3.0 in a flask equipped with a Botan-Stark water separator.
Calculate a mixture of 4 parts (20 mmol) of camphor, 2.9 parts (20 mmol) of 3-chloro-6-pyridazinylhydrazine, 70 parts of benzene and 0.1 parts of 4-toluenesulfonic acid. Boil until water separates.

103-1, then processed as described in the method'
The title compound with a melting point of 0.05 qo (985
%) was obtained. Examples 2-22 Compounds of general formula 1 and their acid addition salts prepared as described above are listed in Table m below.

Table 11n: A = 3-chloro6-pyridazinylhydrazone B = 3-pyridazinylhydrazone D = 3-morpholino-6-pyridazinylhydrazone * = Yield after recrystallization ** = Hydrochloride b = decomposition

Claims (1)

[Claims] 1. A compound having the following general formula I and a physiologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the above formula, R^1 represents hydrogen, chlorine, morpholine ring or N-methylpiperazine ring, and Q is bicycloalkylidene having 6 to 10 carbon atoms, 4 to 10 cycloalkylidene having 1 to 4 carbon atoms, cycloalkenylidene having 4 to 8 carbon atoms, or alkylidene having 1 to 4 carbon atoms substituted by bicycloalkenyl having 6 to 8 carbon atoms. where R^2 is hydrogen, alkyl having 1 to 4 carbon atoms, carboxyl or a group: -COO
R^4 (where R^4 represents alkyl having 1 to 4 carbon atoms), R^3 is hydrogen, 1 or 2 alkyl having 1 to 4 carbon atoms, Or 2~
represents alkenyl having 6 carbon atoms. 2. The compound according to claim 1, which is cyclohexiderine-(3-morpholino-6-pyridazinyl)hydrazone or a physiologically acceptable salt thereof. 3. The compound according to claim 1, which is 2-(ethoxycarbonyl)-1-cyclohexiderine-(3-morpholino-6-pyridazinyl)hydrazone or a physiologically acceptable salt thereof.